PROJECT ABSTRACT Hepatocellular carcinoma (HCC) is the major type of primary liver cancer with increased incident rate the in the US. Treatment options for HCC are still very limited and not effective. The overall survival rate of patients with advanced HCC remains very poor. Cabozantinib is a multi-kinase inhibitor which targets c-MET, VEGFR1/2, AXL, MER and ROS1. Cabozantinib is recently approved by FDA as the second line treatment option for advanced HCC patients who has advanced with Sorafenib treatment. However, the molecular mechanisms underlying Cabozentinib efficacy in HCC is poorly understood. In our recent studies, we investigated therapeutic efficacy of Cabozantinib in a panel of 14 human HCC cell lines as well as 4 types of oncogene driven HCC mouse models (c-Met/?-Catenin, Akt/c-Met, Akt/Ras and c-Myc). We demonstrated that Cabozantinib suppressed HCC cell growth in culture with variable IC50 values. The sensitivities of Cabozantinib correlated with p-MET and p-ERK expression in HCC cell lines. In vivo, we found that Cabozantinib treatment led to stable disease in c-Met/?-Catenin and Akt/c-Met mouse HCCs, but it showed no efficacy towards AKT/Ras and c-Myc mouse HCCs. At the cellular levels, Cabozatintinib inhibited tumor cell proliferation in c-Met/?-Catenin and Akt/c- Met HCC, but not in AKT/Ras and c-Myc HCC. Mechanistically, we demonstrate that Cabozatintinib effectively inhibited p-MET and p-ERK, and induced p21 expression, but did not affect not p-AKT/mTOR signaling in c- Met/?-Catenin and Akt/c-Met mouse HCC. Importantly, we discovered that Cabozantinib treatment led to increased PD-L1 expression in c-Met/?-Catenin HCC. Based on these preliminary data, we hypothesize that Cabozantinib may be combined with mTOR inhibitors or anti-PD-L1 antibodies for improved efficacy against HCC. The hypothesis will be tested in the following two specific aims. In Aim 1, we will investigate whether Cabozantinib synergizes with MLN0128 for HCC treatment; and in Aim 2. To determine the therapeutic efficacy of combined Cabozantinib with anti-PD-L1 antibody in mouse HCC. Altogether, the application fits well with the R03 grant mechanism for pilot experiments and small, self-contained research projects. The proposal is the first to investigate the therapeutic efficacy of Cabozantinib based combination therapy against HCC in preclinical settings. Our studies are highly significant, as the data will provide support to examine Cabozantinib combination therapy in clinical trials. The results will also likely provide novel mechanistic insight into the combination therapies and possible biomarkers for selecting HCC patients who will likely benefit from Cabozantinib based combination therapies.